Prediction of protein–ligand binding affinities using multiple instance learning

Abstract

Accurate prediction of protein–ligand binding affinities for lead optimization in drug discovery remains an important and challenging problem on scoring functions for docking simulation. In this paper, we propose a data-driven approach that integrates multiple scoring functions to predict protein–ligand binding affinity directly. We then propose a new method called multiple instance regression based scoring (MIRS) that incorporates unbound ligand conformations using multiple scoring functions. We evaluated the predictive performance of MIRS using 100 protein–ligand complexes and their binding affinities. The experimental results showed that MIRS outperformed the 11 conventional scoring functions including LigScore, PLP, AutoDock, G-Score, D-Score, LUDI, F-Score, ChemScore, X-Score, PMF, and DrugScore. In addition, we confirmed that MIRS performed well on binding pose prediction. Our results reveal that it is indispensable to incorporate unbound ligand conformations in both binding affinity prediction and binding pose prediction. The proposed method will accelerate efficient lead optimization on structure-based drug design and provide a new direction to designing of new scoring score functions.